The present invention concerns a pharmaceutical preparation for the treatment of Friedreich's ataxia and for the treatment or prevention of pathologies related thereto.
The term ataxia is used in medicine to identify a lack of motor coordination. In fact, a person affected by ataxia loses his/her harmony of movement. Said term also refers to a group of rare, progressive and seriously invalidating diseases of the central nervous system. Said pathologies can stem from inflammatory, infective, metabolic and tumoural causes, but the degenerative and hereditary forms are the most frequent. Of these, the most common form is Friedreich's ataxia (FRDA) which affects one in 50,000 people; it is the dominant autosomal-recessive form in terms of frequency.
The pathology is caused by expansion of the GAA triplet in the gene codifying for a protein called frataxin (chromosome 9q13). The most common gene mutation is the repetition of the GAA triplet located in the first intron of the gene. The sequence of these nucleotide bases, which usually has a maximum of 40 triplets in normal individuals, expands to a few hundred in patients affected by the pathology. The effect is a marked reduction in the RNA level of the frataxin and in the quantity of frataxin expressed, even though a very small quantity continues to be produced.
Frataxin is a mitochondrial protein involved in the homeostasis of iron inside the mitochondria. It has been observed that there is a correlation between the disease and the size of expansion of the GAA triplet. From the biological point of view, the quantity of frataxin produced is inversely proportional to the dimensions of the expansion. From the clinical point of view, the age at which the diseases occur depends on the residual quantity of normal protein produced.
Experimental studies on micro organisms, such as yeast, have shown that destruction of the frataxin gene causes:                a marked increase in the concentration of iron in the mitochondria;        an increase in sensitivity to oxidising factors;        loss of the mitochondrial function, or a deficit in the cell respiratory function.        
There is evidence that in the human disease there is increased oxidative stress and the two possible treatments, at the moment at least, are:                removal of the excess iron from the mitochondria, an approach requiring suitable non-toxic drugs which are not yet available; and        the use of anti-oxidant drugs which, although generally well tolerated, are nevertheless toxic for the organism, albeit at a low level.        
The antioxidant drugs constitute a very broad and diverse family of medicaments and it could be extremely difficult to determine the most appropriate drug for this disease.
From the clinical point of view, FRDA usually occurs in infancy or adolescence, and less frequently in adults. Characterised by a progressive loss of motor coordination, the first symptoms are difficulty in running and in sports activities in general. The lower limbs are generally the first to be affected, causing instability during walking. Subsequently problems with coordination of the hands and with speech occur. Although the disorders are progressive, the course of the illness is variable. Many patients nevertheless become confined to a wheelchair.
Other common symptoms of FRDA are pes cavus, i.e. feet with very high arches, which usually does not require any particular treatment, and scoliosis, i.e. curvature of the spine, which must be kept under control as it can worsen during adolescence. Failing cure, symptomatic treatment must be provided aimed at preventing complications. It is essential to combat scoliosis in order to maintain the seated position and respiratory function.
90% of people affected by FRDA have heart problems, such as:                increased cardiac frequency;        thickening of the walls of the ventricular septum;        electrocardiogram alterations (ECG).        
It is therefore important for patients to have an electrocardiogram and an echocardiogram once a year. These alterations can be controlled, if necessary, by specific drugs such as ibedenone, which belongs to the category of the anti-oxidants. Although 85% of children treated with ibedenone presented an improvement in some of the symptoms, its benefits at neurological level were practically nil.
20% of patients develop diabetes mellitus and periodically checks on glycaemia in the blood are therefore recommended. This disorder can initially be controlled simply via a balanced diet or tablets. Diabetes can sometimes be the first symptom of FRDA.
Currently there is no evidence of an effective pharmacological therapy. Despite the numerous research studies carried out, no treatment is available at present to cure FRDA or slow down its progress.
A known pharmacological agent derived from benzothiazine is diazoxide or 7-chloro-3-methyl-4H-1,2,4 benzothiadiazine 1,1-dioxide. The molecule has the following structural formula

and is an activator of the K+ channels, causing the opening of said channels.
In medical practice said pharmacological agent is used for example in the treatment of acute hypertension.
As an antihypertensive agent, diazoxide is administered intravenously and its effect has a very variable duration (from a few hours to several days). It performs a muscle relaxant action on the hypertensive arterioles by opening the potassium channels, resulting in hyperpolarisation of the cell membranes of the vasal smooth muscles. Diazoxide binds the plasmatic proteins and is eliminated partly via the kidneys after metabolization in the liver, but due to its non-optimal pharmacodynamic characteristics, it is used as an emergency drug.